It is known that oxygen-derived radical species are important mediators of several forms of tissue damage, such as ischemic and traumatic injuries to organs and tissues, inflammatory responses and injuries which result from the intra-cellular metabolism of chemicals and drugs. In particular, oxygen-derived radical species have been suggested as destructive forces in such maladies as head and spinal cord injury, stroke, shock, Parkinsonism, muscular dystrophy, emphysema, ARDS (acute respiratory distress syndrome), asthma, aging, post-myocardial infarct tissue destruction, drug toxicity, radiation damage, transplant rejection and burn damage.
In addition to their adverse effects on various other body tissues, oxidation reactions can also cause damage to the eye. It is known, for example, that the aqueous humor of the eye is rich in hydrogen peroxide and that the anterior tissues bathed by the aqueous humor exist in an extraordinarily oxidative environment. It is further known that prolonged exposure of the eye to light of certain wavelengths can cause harm to anterior, posterior and other tissues of the eye. Indeed, prolonged exposure to light produces oxidative damage in many tissues such as the lens, retina and retinal pigmented epithelium. Additionally, chronic exposure to light and to an oxidative environment is believed to induce cumulative damage, which, depending on the severity of the exposure and the susceptibilities of the individual exposed can result, in the best of cases, in normal aging and discomfort and, in the worst of cases, in pathological disorders and loss of vision.
In addition to light exposure, such a cascade leading to the production of harmful oxidative species is initiated by inflammation, by trauma, by ischemia, by hemorrhaging by stimulation by a variety of drugs and endogenous cell regulators, by pressure exertion on tissues as occurs diurnally as a result of intraocular pressure changes in the anterior chamber of the eye, and indeed by a host of processes both normal and abnormal that occur continuously in the eye. Polyunsaturated fatty acids are also readily subjected to chemical (non-enzymatic) oxidation to yield hydroperoxides, hydroxy fatty acids and malondialdehyde, materials which can contribute to the overall damage that accumulates with time.
Thus, oxidative processes are now known to a play a role in age-related cataracts, light-induced retinal damage, other retinopathies such as diabetic retinopathy and age-related macular degeneration, inflammatory damage (such as that seen in uveitis), vascular leakage and edema (as in cystoid macular edema), accidental or surgical trauma, angiogenesis, corneal opacities, retrolental fibroplasia and some aspects of glaucoma.
To counteract the harmful effects of the oxidative processes described above, the body naturally produces a number of defensive compounds such as .alpha.-tocopherol (vitamin E, which is an antioxidant), ascorbic acid, glutathione, catalase and superoxide dismutase. Thus, vitamin E, is known to be a scavenger of both lipid peroxyl radicals and oxygen radicals, as well as to have a membrane-stabilizing action. Indeed, it is believed that chronic dietary vitamin E supplementation can attenuate postischemic cerebral (hypoperfusion) by inhibiting the lipid peroxidative process.
In order to enhance the eye's ability to protect from damaging oxidative processes such as can occur with aging or due to a sudden trauma, it has been proposed to supply vitamin E to the eye by oral administration in view of its known ability to inhibit oxidative processes. Vitamin E does scavenge free radicals and function as an antioxidant. However, it must be given chronically to have any effect. Moreover, even when administered chronically with other antioxidants, such as glutathione and vitamin C, the results are at best mixed.
A group of 21-aminosteroids has been found to act as antioxidants, and some aminosteroids have been employed intravenously, intraperitoneally and orally in the treatment of central nervous system injury, head and spinal injury, and edema associated with acute stroke. It has been reported that intravenous administration of a citrate buffered saline solution of 0.15 % by weight of U-74600F for treatment of spinal cord or brain injury has been effective to arrest lipid peroxidation therein. It is also known that in performing toxicology studies with various drugs, polysorbate 80 and hydroxypropylcellulose and the like can be used as suspending agents in low viscosity formulations.
International Publication No. WO 87/01706, published Mar. 26, 1987, which discloses a number of aminosteroids and their therapeutic use in a variety of contexts, as well as administration techniques and dosages, does not disclose treatment or prevention of ophthalmic diseases or disorders. Nor does it disclose topical application to the eye or administration by intraocular injection. Moreover, prior art formulations which cannot be comfortably and effectively applied to the eye have limited applicability.
Applicants' great grandparent application Serial No. 07/537,062, now U.S. Pat. No. 5,124,154, discloses methods and compositions which are designed to enhance the ability of the tissues of the eye to respond to trauma, to aging, to surgery, to the threat of glaucoma by increasing intraocular pressure, to the potential loss of vision from progression of macular degeneration and the like by supplementing, both acutely and chronically, the natural ability of the eye to resist oxidative damage. In one aspect, the '154 invention discloses methods of arresting processes (particularly oxidation processes) causing damage to the eye of a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, wherein certain amino-substituted steroids which function as a therapeutic agent (particularly an antioxidant agent) are administered in an inert vehicle to the eye tissue by intraocular injection or topically. In another aspect, the '154 invention discloses methods of preventing or treating ophthalmic diseases or disorders in a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, wherein an ophthalmically effective amount of certain amino-substituted steroids which function as a therapeutic agent (particularly an antioxidant agent) is administered, in an inert vehicle, to arrest processes (particularly oxidation processes) damaging to the eye. Compositions useful in the disclosed methods are also described.
The aminosteroids disclosed in International Publication No. WO 87/01706 and great grandparent U.S. Ser. No. 07/537,062 (now U.S. Pat. No. 5,124,154), as well as in parent Ser. No. 07/933,574, now U.S. Pat. No. 5,209,926 thus are valuable therapeutic agents, particularly as a consequence of their antioxidant activity. However, the aminosteroids suffer from stability problems and they can cause irritation. Moreover, because they are potent antioxidants, the aminosteroids are especially sensitive to oxidative degradation; moreover, these compounds are subject to hydrolytic degradation and rearrangement. Such instability can severely limit the usefulness of pharmaceutical compositions containing the aminosteroids, for example, by drastically shortening the shelf-life of the formulations and/or requiring stringent control of storage conditions. The aminosteroids also are known to be highly insoluble in water, even in salt form; such insolubility can seriously hamper efforts to utilize the compounds to their full potential. There is thus a serious need for improved pharmaceutical compositions comprising the aminosteriods and for methods for the stabilization or combined stabilization and solubilization of such pharmaceutical compositions and for amelioration of irritation.
Sustained release ophthalmic formulations of an ophthalmic drug and a high molecular weight polymer to form a highly viscous gel have been described in Schoenwald et al U.S. Pat. No. 4,271,143, issued Jun. 2, 1981 and Schoenwald et al U.S. Pat. No. 4,407,792, issued Oct. 4, 1983.
U.K. Patent Application GB 2007091 A, published May 16, 1979, describes an ophthalmic composition in the form of a gel comprising an aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance and an ophthalmic drug, the gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20.degree. C.
U.K. Patent Application GB 2013084 A, published Aug. 8, 1979, describes an aqueous gel for application to the conjunctival sac of the eye comprising an ophthalmic drug and a polymer having carboxylic or anhydride functional groups and a molecular weight in excess of 1,000,000, such as carboxypolymethylene, carboxyvinyl and ethylene maleic anhydride polymers.
Robinson U.S. Pat. No. 4,615,697, issued Oct. 7, 1986, discloses a controlled release composition and method of use based on a bioadhesive and a treating agent, such as an anti-inflammatory agent. The bioadhesive is a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer having a plurality of repeating units of which about 80 percent contain at least one carboxyl functionality and a cross-linking agent which is substantially free from polyalkenyl polyethers.
Davis et al copending application Ser. No. 07/544,518, filed Jun. 27, 1990 now U.S. Pat. No. 5,192,535 and assigned to the assignee hereof, describes formulation of lightly cross-linked polymers, preferably ones prepared by suspension or emulsion polymerizing at least about 90% by weight of a carboxyl-containing monoethylenically unsaturated monomer such as acrylic acid with from about 0.1% to about 5% by weight of a polyfunctional, and preferably difunctional, cross-linking agent such as divinyl glycol (3,4- dihydroxy-1,5-hexadiene), having a particle size of not more than about 50 .mu.m in equivalent spherical diameter, with an ophthalmic medicament, e.g., the steroid fluorometholone, into suspensions in aqueous medium in which the amount of polymer ranges from about 0.1% to about 6.5% by weight, based on the total weight of the aqueous suspension, the pH is from about 0 3.0 to about 6.5, and the osmotic pressure (osmolality or tonicity) is from about 10 mOsM to about 400 mOsM. These new topical ophthalmic medicament delivery systems have suitably low viscosities which permit them to be easily administered to the eye in drop form, and hence to be comfortably administered in consistent, accurate dosages. These suspensions will rapidly gel in the eye after coming into contact with the eye's tear fluid to a substantially greater viscosity than that of the originally-introduced suspension and thus remain in place for prolonged periods of time to provide sustained release of the ophthalmic medicament. See International Publication Number WO 92/00044 published Jan. 9, 1992, which claims priority from U.S. Ser. No. 07/544,518 and see also International Publication No. WO 89/06964, published Aug. 10, 1989, which claims the priority of the parent and grandparent applications upon which U.S. Ser. No. 07/544,518 is based.
It has not been heretofore suggested, however, that lightly cross-linked carboxy-containing polymers could be used to stabilize aminosteroids in pharmaceutical formulations. Furthermore, it has not been suggested that cyclodextrins and lightly cross-linked carboxy-containing polymers would be compatible with on another. It was also not known that aminosteroids disclosed in International Publication No. WO 87/01706 and great grandparent U.S. Ser. No. 07/537,062 (now U.S. Pat. No. 5,124,154) would be compatible or stable with lightly cross-linked carboxy-containing polymers or the combination of such polymers with cyclodextrins.
Cyclodextrins are cyclic oligosaccharides. The most common cyclodextrins are .alpha.-cyclodextrin, which is composed of a ring of six glucose residues; .beta.-cyclodextrin, which is composed of a ring of seven glucose residues; and .gamma.-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes with drugs have been reported. .beta.-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility (about 1.8% w/v at 25.degree. C.) and attendant nephrotoxicity have limited its use in the pharmaceutical field.
Attempts to modify properties of the natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)-.beta.-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, .beta.-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive review of cyclodextrins and their use in pharmaceutical research, see Pitha et al, in Controlled Drug Delivery, ed. S. D. Bruck, Vol. I, CRC Press, Boca Raton, Fla., 125-148 (1983). For an even more recent overview, see Uekama et at, in CRC Critical Reviews in Therapeutic: Drug Carrier Systems, Vol. 3 (1), 1-40 (1987); Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomedical Division), 1987, 181-194; and Pagington, Chemistry in Britain, May 1987, 455-458.
Inclusion complexes of .alpha.-, .beta.- or .gamma.-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. These descriptions include those documents summarized in Bodor U.S. Pat. Nos. 4,983,586 and 5,024,998, incorporated by reference herein in their entireties and relied upon. Particular reference may be made to Lipari U.S. Pat. No. 4,383, 992, which describes inclusion complexes of .beta.-cyclodextrin itself with a variety of steroidal hormones (corticosteroids, androgens, anabolic steroids, estrogens and progestagens). The complexes are said to have improved water solubility and increased therapeutic response in the eye. However, as noted above, .beta.-cyclodextrin has low aqueous solubility (about 1.8% w/v at 25.degree.) with attendant nephrotoxicity.
Hydroxypropyl-.beta.-cyclodextrin and its preparation by propylene oxide addition to .beta.-cyclodextrin were described in Gramera et al U.S. Pat. No. 3,459,731 over 20 years ago. (Gramera et al also described the analogous preparation of hydroxyethyl-.beta.-cyclodextrin by ethylene oxide reaction with .beta.-cyclodextrin.) Much more recently, Pitha and co-workers have described the improved preparation of this cyclodextrin derivative and its effects on the dissolution of various drug molecules. Pitha U.S. Pat. No. 4,596,795, dated Jun. 24, 1986, describes inclusion complexes of sex hormones, particularly testosterone, progesterone and estradiol, with specific cyclodextrins, preferably hydroxypropyl-.beta.-cyclodextrin and poly-.beta.cyclodextrin. The complexes enable the sex hormones to be successfully delivered to the systemic circulation via the sublingual or buccal route; the effectiveness of this delivery is believed to be due to "the high dissolution power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure of their complexes with steroids, and their low toxicity and irritancy of mouth tissue". Success with other cyclodextrins, including poly-.gamma.-cyclodextrin and hydroxypropyl-.gamma.-cyclodextrin, have also been noted in the Pitha patent. See also Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990, concerning the same and related studies. Pitha et al also describe in the J. Pharm. Sci. publication the storage stability of tablets containing a testosterone/hydroxypropyl-.beta.-cyclodextrin complex and the lack of toxicity of the cyclodextrin derivative itself, as well as the importance of the amorphous nature of the cyclodextrin derivatives and their complexes with drugs in improving dissolution properties.
The improved, optimized preparation and purification of hydroxypropyl-.beta.-cyclodextrin has been described by Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986). In the same publication, the authors have described increased water solubility for 32 drugs in concentrated (40 to 50%) aqueous solutions of hydroxypropyl-.beta.-cyclodextrin; among the drugs for which the authors have reported improved solubilization are dexamethasone, estradiol, estriol, ethinylestradiol-3-methyl ether, ethisterone, 17-methyltestosterone norethindrone, progesterone, spironolactone and testosterone. The authors indicated this to be an extension of their earlier work with hydroxypropyl-.beta.-cyclodextrin which was previously found effective for oral administration of the sex hormones to humans. Their later work reported in Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986), has also been described in Pitha U.S. Pat. No. 4,727,064, dated Feb. 23, 1988. That patent claims a composition containing an amorphous complex of cyclodextrin and a drug, and a method of producing a stabilizing amorphous complex of a drug and a mixture of cyclodextrins comprising (1) dissolving an intrinsically amorphous mixture of cyclodextrin derivatives which are water soluble and capable of forming inclusion complexes with drugs in water; and (2) solubilizing lipophilic drugs into aqueous media to form a solution and form a solubilized drug/cyclodextrin complex. The patent describes the preparation of various substituted amorphous cyclodextrins, including hydroxypropyl-.beta.-cyclodextrin and hydroxypropyl-.gamma.-cyclodextrin, the latter by analogous condensation of propylene oxide and .gamma.-cyclodextrin.
Uekama et al, CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), 1-40 (1987), have described the characteristics of various cyclodextrins, including hydroxypropyl-.beta.-cyclodextrin. The authors have presented data showing improved solubilization in water in the presence of 15 mg/mL of hydroxypropyl-.beta.-cyclodextrin for the drugs carmofur, diazepam, digitoxin, digoxin, flurbiprofen, indomethacin, isosorbide dinitrate, phenytoin, prednisolone, progesterone and testosterone. Uekama et al have indicated that cyclodextrins at sufficiently high concentrations cause hemolysis, and that the methylated cyclodextrins have higher hemolytic activity than the natural cyclodextrins. Hydroxypropyl-.beta.-cyclodextrin is said to cause hemolysis beginning at 4.5 mM. The authors have further indicated that parenteral administration of large doses of cyclodextrins should be avoided, but that ".gamma.-cyclodextrin and hydroxypropyl-.beta.-cyclodextrin seem to be useful in drug solubilization for injections and liquid preparations used for mucous membranes."
JANSSEN PHARMACEUTICA N.V.'s International Patent Application No. PCT/EP84/00417, published under International Publication No. WO85/02767 on Jul. 4, 1985, has described pharmaceutical compositions comprising inclusion compounds of drugs, which are unstable or only sparingly soluble in water, with partially etherified-.beta.-cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups. Among the cyclodextrin derivatives contemplated is hydroxypropyl-.beta.-cyclodextrin, while the drugs include nonsteroidal anti-rheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole and triazole. Pharmaceutical compositions described in WO 85/02767 include oral, parenteral and topical formulations, with 4 to 10% solutions of cyclodextrin derivatives being used to solubilize various drugs. Improved solubilities of indomethacin, digitoxin, progesterone, dexamethasone, hydrocortisone and diazepam using 10% hydroxypropyl-.beta.-cyclodextrin are reported.
The preparation of amorphous water-soluble cyclodextrin derivatives, including 2-hydroxyethyl-.beta.-cyclodextrin, 3-hydroxypropyl-.beta.-cyclodextrin and 2-hydroxypropyl-.gamma.-cyclodextrin, is described by Irie et al, Pharmaceutical Research, Vol. 5, No. 11, 1988, 713-717. That report also addresses the distribution of the substituents among the glucose residues of the cyclodextrin ring.
A pharmaceutical evaluation of hydroxyalkyl ethers of .beta.-cyclodextrin has been reported by Yoshida et at, International Journal of Pharmaceutics 46, 1988, 217-222. Aqueous solubilities, surface activities, hemolytic activity and local irritancy are reported. The data suggest that hydroxyalkyl-.beta.-cyclodextrins overcome many of the undesirable characteristics of .beta.-cyclodextrin usage in pharmaceuticals.
JANSSEN PHARMACEUTICA N.V.'s European Patent Application No. 86200334.0, published under EPO Publication No. 0197571 on Oct. 15, 1986, describes .gamma.-cyclodextrin derivatives which are .gamma.-cyclodextrin substituted with C.sub.1 -C.sub.6 alkyl, hydroxy C.sub.1 -C.sub.6 alkyl, carboxy C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkyloxycarbonyl C.sub.1 -C.sub.6 alkyl or mixed ethers thereof. Among the specific derivatives named are hydroxypropyl-.gamma.-cyclodextrin and hydroxyethyl-.gamma.-cyclodextrin. Compositions comprising the cyclodextrin derivatives and a drug are also described. See also corresponding Muller U.S. Pat. No. 4,764,604, dated Aug. 16, 1988.
Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomedical Division), 1987, 181-194, has described the effects on bio-pharmaceutical properties of maltosyl and glucosyl cyclodextrin derivatives, as well as hydroxypropyl and other hydrophilic cyclodextrin derivatives, including enhanced drug absorption. The mechanism of enhancing drug absorption is described and the apparent stability constants for inclusion complexes of various drags with .beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin, hydropropyl-.beta.-cyclodextrin and maltosyl -.beta.-cyclodextrin are given. Drugs studied with these cyclodextrins include prednisolone, progesterone, spironolactone and testosterone.
Koizumi et al, Chem. Pharm. Bull. 35 (8), 3413-3418 (1987), have reported on inclusion complexes of poorly water-soluble drugs with glucosyl cyclodextrins, namely 6-O-.alpha.-D-glucosyl-.alpha.-CD (G.sub.1 -.alpha.-CD), 6-O-.alpha.-D-glucosyl-.beta.-CD (G.sub.1 -.beta.-CD) and 6A, 6.sup.D -di-O-.alpha.-D-glucosyl-.beta.-CD (2G.sub.1 -.beta.-CD).
Okada et al, Chem. Pharm. Bull. 36(6), 2176-2185 (1988), have reported on the inclusion complexes of poorly water-soluble drugs with maltosyl cyclodextrins, namely 6-O-.alpha.-maltosyl-.alpha.-CD (G.sub.2 -.alpha.-CD), 6-O-.alpha.-maltosyl-.beta.-CD (G.sub.2 -.beta.-CD), 6-O-.alpha.-maltosyl-.gamma.-CD (G.sub.2 -.gamma.-CD), 6-O-.alpha.-maltotriosyl-.alpha.-CD (G.sub.3 -.alpha.-CD), 6-O-.alpha.-maltotriosyl-.beta.-CD (G.sub.3 -.beta.-CD) and 6-O-.alpha.-maltotriosyl-.gamma.-CD (G.sub.3 -.gamma.-CD).
Yamamoto et al, in International Journal of Pharmaceutics 49, 163-171 (1989), have described physicochemical properties of branched .beta.-cyclodextrins such as glucosyl-.beta.-cyclodextrin, maltosyl-.beta.-cyclodextrin and dimaltosyl-.beta.-cyclodextrin, and their inclusion characteristics. Those authors report that the branched .beta.-cyclodextrins are better solubilizers for poorly water-soluble drugs and have less hemolytic activity than .beta.-cyclodextrin itself, and they suggest that glucosyl-.beta.-cyclodextrin and maltosyl-.beta.-cyclodextrin may be especially useful in parenteral preparations.
The patent literature reflects much recent work on the branched cyclodextrins carried out by Japanese workers, as discussed below.
Japanese Kokai 63-135402 (TOKUYAMA SODA KK), published Jun. 7, 1988, describes compositions consisting of maltosyl-.beta.-cyclodextrin and at least one of digitoxin, nifedipine, flurubiprophen, isosorbide nitrate, phenytoin, progesterone or testosterone. The compositions have improved water solubility and reduced erythrocyte destruction, are safe for humans and can be used as injections, eye drops, syrups, and for topical and mucous membrane application.
Japanese Kokai 62-281855 (DAIKIN KOGYO KK), published Dec. 7, 1987, describes stable, water-soluble inclusion compounds of maltosyl-.beta.-cyclodextrin with a variety of vitamins and hormones, e.g. steroid hormones such as prednisolone, hydrocortisone and estriol. These lipophilic vitamins and hormones can thus be used as aqueous solutions.
Japanese Kokai 63-036793 (NIKKEN CHEM KK), published Feb. 17, 1988, describes the preparation of dimaltosyl-.gamma.-cyclodextrin and its general use in medicines.
Japanese Kokai 62-106901 (NIKKEN CHEM KK), published May 18, 1987, describes the preparation of diglucosyl-.beta.-cyclodextrin and its general use for pharmaceuticals.
Japanese Kokai 61-236802 (NIKKEN CHEM KK), published Oct. 22, 1986, describes the preparation of maltosyl-.gamma.-cyclodextrin and its general use with drugs.
Japanese Kokai 61-197602 (NIKKEN CHEM KK), published Sep. 1, 1986, describes the preparation of maltosyl-.beta.-cyclodextrin and its expected use in medicines.
Japanese Kokai 61-070996 (NIKKEN CHEM KK), published Apr. 11, 1986, describes the preparation of maltosyl-.alpha.-cyclodextrin and its general use in pharmaceuticals.
Japanese Kokai 63-027440 (SANRAKU OCEAN), published Feb. 5, 1988, describes compositions containing a water-insoluble or slightly soluble drug together with glucosylated branched cyclodextrin. Among the drags mentioned are steroid hormones.
Japanese Kokai 62-164701 (SHOKUHIN SANGYO BIO), published Jul. 21, 1987, describes the preparation of diglucosyl-.alpha.-cyclodextrin and its general use in medicine.
Japanese Kokai 62-003795 (TOKUYAMA SODA KK), published Jan. 9, 1987, describes production of glucose and maltoligosaccharide (2-4 glucose units) derivatives of .alpha.-, .beta.- and .gamma.-cyclodextrin and their use as stabilizers for pharmaceuticals.
Bodor U.S. Pat. Nos. 5,002,935, issued Mar. 26, 1991,. and U.S. Pat. No. 5,017,566, issued May 21, 1991, relate to stabilizing the reduced, dihydropyridine forms of dihydropyridine.revreaction.pyridinium salt redox systems for brain-targeted drug delivery by complexation with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrins. The complexes also provide a means for increasing the ratio of initial brain to lung concentrations of drug, leading to decreased toxicity. In selected instances, improved water solubilities are noted as well. In a preferred aspect, the redox system is a redox carrier system and the reduced, dihydropyridine form can be represented by the formula [D-DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine.revreaction.pyridinium salt redox carrier. The "centrally acting" drug species is broadly defined and includes many classes of drugs, including steroids and, specifically, anti-inflammatory adrenal cortical steroids such as hydrocortisone, betamethesone, cortisone, dexamethasone, flumethasone, fluprednisolone, meprednisone, methyl prednisolone, prednisolone, prednisone, triamicinolone, cortodoxone, fludrocortisone, flurandrenolone acetonide (flurandrenolide), paramethasone and the like. The "dihydropyridine carrier" or "[DHC]" is defined as any nontoxic carder moiety comprising, containing or including the dihydropyridine nucleus, the only criterion being capacity for BBB penetration and in vivo oxidation to the corresponding quaternary pyridium salt. Among the specific redox carder drugs for complexation with cyclodextrins in accord with the Bodor patents are a number of steroid derivatives, including the derivatives of dexamethasone and hydrocortisone shown below: ##STR1##
The aforenoted Bodor patents propose complexation with the specific cyclodextrin derivatives named in the preceding paragraph as a means for overcoming the stability problems from which the dihydropyridine-containing redox compounds suffer; the patents note that even in the dry state, the redox compounds are very sensitive to oxidation as well as to water addition. Such complexation is also proposed in the Bodor patents as a means for providing better brain to lung ratios of the redox compounds by preventing their precipitation out of solution at the injection site or in the lungs. Successful solubilization of a number of redox compounds is noted; however, Bodor indicates that such results are not universal. For example, in the case of estradiol, the redox derivative has about the same solubility in aqueous 50% hydroxypropyl-.beta.-cyclodextrin as has the parent drug; in the case of norethindrone, the redox drug has less than 1% of the solubility in aqueous 50% hydroxypropyl-.beta.-cyclodextrin displayed by the parent drug.
Bodor U.S. Pat. No. 4,983,586, issued Jan. 8, 1991, and U.S. Pat. No. 5,024,998, issued Jun. 18, 1991, relate to pharmaceutical formulations for parenteral use. Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrins, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration. The parenteral solutions contain from about 20% to about 50% of the selected cyclodextrin(s). The drugs may be the dihydropyridine forms of dihydropyridine.revreaction.pyridinium salt redox systems (as noted above in connection with the Bodor '935 and '566 patents) or other poorly soluble or unstable drugs of many types, including steroids. Anti-inflammatory steroids such as dexamethasone, hydrocortisone and prednisolone are mentioned.
Recently, the solubilizing and stabilizing effects of hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) on drugs have been reviewed by Thorsteinn Loftsson, Pharm. Ztg. Wiss, 4/136: 5-10 (1991). Solubility enhancement for many drugs in water has been accomplished by means of complexation with HP.beta.CD. The solubility of dexamethasone was increased 5,500 times and intravenous administration of the dexamethasone-HP.beta.CD complex gave higher initial plasma levels of dexamethasone than those obtained after dexamethasone phosphate dosing. The authors further note that transdermal/topical nonocclusive aqueous vehicle systems are suggested to avoid side-effects of occlusive systems, and that the improved water solubility of many lipophilic drugs in aqueous HP.beta.CD solutions makes the nonocclusive systems possible. Transdermal delivery of the steroids 17.beta.-estradiol, hydrocortisone and testosterone in aqueous HP.beta.CD solutions have been reported. See also Loftsson et at, Acta Pharm. Nord. 1(4), 185-193 (1989), which describes the effects of 2-hydroxypropyl -.beta.-cyclodextrin on the aqueous solubility of drugs, including dexamethasone, and the transdermal delivery of 17.beta.-estradiol. It has also been suggested that the hydroxy-propyl derivatives of betacyclodextrin could be useful in solubilizing amino-substituted steroid therapeutic agents of the type disclosed in the aforementioned International Publication No. WO 87/01706 and U.S. Pat. No. 5,124,154.
It has not been heretofore suggested, however, that hydroxyalkylated or branched cyclodextrin derivatives could be advantageously combined with lightly cross-linked carboxy-containing polymers in pharmaceutical formulations of amino-substituted steroid therapeutic agents of the type disclosed in the aforementioned International Publication No. WO 87/01706 and U.S. Pat. No. 5,124,154 to afford remarkably stable compositions whose drug release rate could be finely controlled.